X-ray contrast agents comprising symmetrical bifunctional analogs of nu-acyl derivatives of 2, 4, 6 triiodo-3-amino benzoic acid



X-RAY CONTRAST AGENTS COMPRISING SYMMETRICAL BIFUNCTIONAL ANALOGS OF NACYL DERIVATIVES OF 2,4,6 TRIIODO-B-AMINO BENZOIC ACID Filed. Oct. 26, 1956 Sept. 23, 1958 H PRIEWE EIAL 2,353,424

mmvroRs. l/ans P v'ewe Rad Rafkowki m r/Amt ATTOR/VEV X-RAY CONTRAST AGENTS COMPRISING SYM- METRICAL BIFUNCTIONAL ANALOGS OF N-ACYL DERIVATIVES OF 2,4,6 TRIIODO-3- AMINO BENZOIC ACID Hans Priewe, Berlin-Steglitz, and Rudi Rutkowski, Hiltrup, Germany, assignors to Schering A. G., Berlin, Germany, a corporation of Germany Application October 26, 1956, Serial No. 618,530

Claims priority, application Germany August 6, 1952 4 Claims. (Cl. 167-95) This invention relates to X-ray contrast agents and their manufacture and in particular to new N-acyl-3- X-ray Contrast Agents.

One object of this invention is to provide new preparations which are excellent, non-irritating, heat sterilizable, X-ray contrast agents that permit X-ray visualization of various parts of the human body, especially of kidney,

bladder and urethra, gall bladder, heart, blood vessels and others.

Still another object of the present invention is-to PI'O vide new X-ray contrast agents of the formula I I I I I NH.OC.A.X.A.OO.NH

(10011 boon wherein X indicates a member selected from the group consisting of oxygen and sulfur and A indicates alkylene radicals having 1 to 3 carbon atoms.

Other objects and advantageous features of this invention will become apparent as the description proceeds. By reaction of 2,4,6-triiodo-3-aminobenzoic acid with nited States Patent acid halides or with ester acid halides or with N-sub:

stituted or unsubstituted amide acid halides of polybasic carboxylic acids, especially of dibasic carboxylic acids such as dibasic alkanoic acids the alkyl chain of which is interrupted by at least one sulfur or oxygen or nitrogen, atom, compounds are obtained which correspond to the above indicated formula.

It has been found that these compounds are good X-ray contrast agents and are especially suitable for X-ray visualization of intraand extrahepatic bile ducts, gall bladder and for examination of function of sphincter oddi.

The compounds can be used in the form of their salts, especially the alkali salts or the salts with non-toxic organic bases.

As is evident, compounds of this type of X-ray agents are characterized by the presence of one or several polyvalent hetero atoms, such as oxygen and/ or sulfur, in the carbon atom chain A. X. A., of the above given formula. Said hetero atoms interrupt said carbon atom chain. Compounds of this type may, of course, also be substituted by other substituents, such as halogen, especially iodine, hydroxyl, oxo, amino groups or functional derivatives of such groups, as stated above.

Compounds of said type having a carbon chain inter- ICC rupted by a hetero atom are, for instance, produced by condensing triiodo amino benzoic acid or functional derivatives of the carboxyl group thereof, with suitable polybasic carboxylic acids, such as acids of the type of diglycolic acid HOOC-=CH CH -OCH +CH -COOH thiodiglycolic acid HOOCCH -S-CH COOH, di-

thiodiglycolic acid HOOC-CH SSCH -COOH,

thiodihydracrylic acid H0OC.CH .CH .S.CH .CH .C0OH

and similar polycarboxylic acids. The following examples serve to illustrate the present invention, without, however, limiting the same'thereto.

Example 1 910 g. of dry 2,4,6-triiodo amino benzoic acid are dissolved with stirring in 4800 cc. of dry, boiling chlorobenzene. A solution of 151.7 g. diglycolic acid dichloride in cc. of dry chlorobenzene is slowly added to said solution and the mixture is further heated for 4-5 hours under reflux until development of hydrogen chloride has ceased. The resulting precipitate is filtered from the warm solution with suction and washed with chlorobenzene and then with ether. The microcrystalline, almost colorless crude product, 942 g., consists of the OL-l'I'lOdlfiCallOH of diglycolic acid di-(3-carboxy- 2,4,6-triiodo anilide) of the formula given hereinafter.

The crude product is suspended, while stirring, in 2.5 liters of pure methanol and a solution of 73 g. of pure sodium hydroxide in the same weight of water, diluted with 675 cc. methanol, is slowly added to this suspension till the acid is dissolved and the pH of this solution reaches 9.0. The solution is allowed to stand at this pH for 15 minutes. The pH is then brought to 4.0 by addition of 10% acetic acid and 17 g. of charcoal are stirred in. After 15 minutes the coal is filtered off and the clear filtrate is slowly added to a stirred solution of 415 cc. of pure, concentrated hydrochloric acid in 4.15 liters of 50% methanol. After /2 hour of stirring and decanting after 1 hour, the precipitate is easily filtered off with suction, washed with little methanol and thoroughly with water, until the thixotropic residue is free of hydrochloric acid. In order to obtain a product of highest purity, this treatment is repeated two times. The resulting pure product, after drying in vacuo at 50 C. still containing one molecule of methanol per two molecules of the acid (plus 4 molecules of water), must be suspended in boiling water and steamed out. The hot suspension is filtered with suction, the white, microcrystalline residue is dried in vacuo at 50 C. togive 860 g. (83.5% of the theoretical yield) of the pure dihydrate of the diglycolic acid di-(3-carboxy- 2,4,6-triiodo anilide), Si-modification.

I I l I +2Hz0 CODE ultraviolet spectrum and extinction as the B-form, but the" infra red spectrum is greatly different (see the accompanying drawing, dia ram A). M. P.: 297/298 C. under decomposition.

The crude a-modification as' described hereinabove is easily transformed in the-B-modification by dissolving the OC-HCid and allowing the solution to stand in alkaline solution for short time, whereafter mineral acids precipitate the ,B-acid. On the other hand, by boiling a suspension of theB-acid in chlorobenzene for 24 hours under reflux, the pure u-acid is obtained. These transformations seem to correspond to hydrate-isomerism.

Example 2 5.6 g. of thiodiglycolic acid dichloride areintroduced dropwise into a boiling solution of 50 g. of 2,4,6-triiodo-3- amino benzoic acid in 150 cc. ofchlorobenzene. After about 3 hours evolution-of hydrochloric acid has ceased. Th'e precipitated crudethiodiglycolic acid di-(3-carboxy- 2,4,6-triiodo anilide) of the formula COOH COOH is filtered'with suction and washed with ether. For purification, the compound is dissolved in N caustic soda solution, filtered over charcoal, andprecipitated with hydrochloric acid; M.- P. 263265 C. (with decomposition), yield: 263 g.

Example 3 206 g. of dry 2,4,6-triiodoamino 'benzoic acid'rare dissolved in lliter of dry, boiling'chlorobenzene andasolir tion of 43 g. thio dihydracrylic acid dichloride in 30 cc..of dry chlorobenzene is added thereto within 30 minutes,

while. stirring. After. 2 hours of furtherboilingzunderi.

refluxthe precipitatedcrude product is filtered with suc:-' tion, washed with chlorobenzene and ether, and dried; The 210 g. ofcrude productare suspendedinwater, dissolved by addition-of 2 N sodium hydroxide solution, treatediwith charcoal, and filtered. The clear filtrate.is stirred in'=N hydrochloric acid, the precipitate isv filtered with suction, and Washed with water free of hydrochloric acid. This procedure is repeated once again,.and after drying on-t'he air 176g. (73% of the theoreticaLyield) of. pure thio-dihydracrylic acid. di (2,4,6-triiodo anilide) monohydrate are obtained. decomposition.

M; P.: 230/232" C. under As reaction components in which the carbon chain is interrupted by a hetero atom, there may be used in the place of thio diglycolic acid. chloride of Example 2 and of diglycolic acid dichloride of Example 1, other halogenides of similar constitution and the corresponding acid ester halogenides, such as; for instance, the halogenides of thio dilactic acid 'y-thio dibutyric acid, thio dihydracrylic acid, cystine, 8- dithio' dipropionic acid, and'others. v

Soluble salts. of these. new X-ray contrast agents are preferably used in aqueous solution whereby the concentration is preferably'betweenabout 30% by volume and about 60% by volume. These solutions are especially adapted for use in intravenous cholangiography.

Of course many other changes and variations in the reaction components used, the reaction conditions, reaction time and temperature employed, the solvents used, the methods of workingupand. of purifying the reaction products and their salts and functional derivatives, and

I I l NH.OC.A.X.A.CO.NH

I I I 1 COOH COOH wherein X indicates a member selected from the group consisting of oxygen andsulfur, and A indicates alkylene radicalshaving' 1"to3 carbon atoms, and the substantially non-toxic salts of' such anacid'with alkali metals, ammonia; alkaline earth metals, and organic bases.

References Cited in the file of this patent UNITED STATES PATENTS 2,606,922 Papa et a1.' Aug. 12, 1952 2,776,241 Priewe et a1 J an. 1, 1957 

4. X-RAY CONTRAST AGENT SELECTED FROM THE GROUP CONSISTING OF AN N-ACYL DERIVATIVE OF 2,4,6-TRIIODO-3-AMINO BENZOIC ACID OF THE FORMULA 